tbuckley/cabot-search huggingface dataset:
Abstract P6-11-05: Carnitine palmitoyltransferase 1A (CPT1A) mediates therapeutic response to endocrine therapy in estrogen receptor positive breast cancer
Authors: Shaimaa Hussein, Michael L. Gatza, Shridar Ganesan
Journal: Cancer Research (2023)

Abstract Breast cancer (BC) is the most commonly diagnosed cancer and second leading cause of cancer-related deaths in women in the United States, with more than 70% of the cases are hormone receptor positive (HR+) disease. Endocrine based therapies (ET) are successfully used, however, 30-50% will acquire ET resistance leading to tumor progression. Since the mechanism of acquired resistance remains unknown for ~60% of patients, identifying novel mechanisms of resistance is essential. We recently reported that carnitine palmitoyltransferase 1A (CPT1A), the rate limiting enzyme in fatty acid oxidation, is overexpressed in aggressive HR+ tumors, including ET resistant patients. We propose that CPT1A level and activity changes the tumor microenvironment to enhance tumorigenesis and contribute to ET resistance. To determine the mechanism by which CPT1A is promoting cell proliferation, tumor microenvironment, cellular signaling and ET resistance, we used a series of in vitro studies incorporating a panel of either endogenously or experimentally derived CPT1A-low and CPT1A-high controls, HR+ breast cancer cell lines as well as their ET resistant counterparts. We determined that CPT1A is upregulated in cell lines that acquire ET resistance. Our analyses demonstrated that levels of CPT1A can affect tumor formation ability in both CPT1A-high and adjacent CPT1A-low tumor cells with concurrent changes in both intra- and inter-cellular signaling which may be essential to promote tumor progression and mediate therapeutic response. This represents a promising step in understanding the mechanisms that promote tumorigenesis and ET resistance in HR+ breast cancer. Citation Format: Shaimaa Hussein, Michael L. Gatza, Shridar Ganesan. Carnitine palmitoyltransferase 1A (CPT1A) mediates therapeutic response to endocrine therapy in estrogen receptor positive breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P6-11-05.
Abstract P3-10-01: Deciphering the heterogeneity of cell cycle in breast cancer and relevance to clinical application of CDK inhibitors
Authors: Erik S. Knudsen, Vishnu M. Kumarasamy, Jianxin Wang, Agnieszka Witkiewicz
Journal: Cancer Research (2023)

Abstract BACKGROUND: Deregulation of cellular proliferation represents a defining hallmark of cancer. The mechanisms driving aberrant cell cycle progression across different breast cancer subtypes is highly diverse and likely contributes to therapeutic resistance in a variety of contexts. The significance of cell cycle heterogeneity is most clear in the context of metastatic HR+/HER2- breast cancer, wherein acquired and intrinsic resistance to CDK4/6 inhibition represents a significant clinical challenge. However, aberrant cell cycle regulatory networks likely further confound the use of targeted therapies in the context of TNBC. METHODS AND RESULTS: We employed unbiased analyses of large number of breast cancer models to decipher the genetic requirements for different CDK and Cyclins which drive proliferation and the significance to response to CDK4/6 inhibitors. Breast cancer cells harbor heterogeneity in the requirement for a given G1/S regulatory CDK or Cyclin. These dependencies are conditioned by the expression of the respective CDK or Cyclin, as well as other gene expression or genetic features present within the tumor that could represent putative biomarkers. In general, conventional dependency for CDK4 and Cyclin D1 is strongest in HR+/HER2- breast cancer models, whereas TNBC exhibits dependency on a variety of different CDK or Cyclin genes. Resistance to CDK4/6 inhibitors in HR+/HER2- breast cancer models, while occurring through a number of different primary mechanisms, functionally deregulates the phosphorylation of RB. However, genetically enforcing RB activation is sufficient to block proliferation, underscoring the opportunity to ameliorate resistance to CDK inhibitory strategies. CRISPR screens in HR+/HER2- and TNBC models are identifying new mediators of sensitivity and resistance to CDK4/6 inhibitors. Inherently, elevated expression of Cyclin E and p16INK4A are associated with resistance to multiple therapeutic approaches, including CDK4/6 inhibitors, but denote a requirement for CDK2. The cell cycle conditions disparately dependent on CDK4/D1 vs. CDK2/E can be visualized by multispectral imaging and used to direct CDK inhibitor based strategies. CONCLUSIONS: Together these studies illustrate the complex nature of breast cancer cell cycles which can confound therapy. However, understanding of this heterogeneity can create new opportunities for precision approaches targeting CDK/Cyclin-dependence therapeutically. Citation Format: Erik S. Knudsen, Vishnu M. Kumarasamy, Jianxin Wang, Agnieszka Witkiewicz. Deciphering the heterogeneity of cell cycle in breast cancer and relevance to clinical application of CDK inhibitors [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P3-10-01.
Abstract P4-03-32: Association between androgen receptor expression and recurrence free survival among locally advanced triple negative breast. Real world data from a single Institution in Mexico City
Authors: Eder Araiza Alvarado, Claudia Haydee Arce Salinas
Journal: Cancer Research (2023)

Abstract Background The androgen receptor (AR) is expressed in 12-41% of the TNBC, contributes with differentiation, proliferation, apoptosis, and angiogenesis; its expression is associated with better recurrence free survival (RFS) and overall survival (OS). Objective The aim is to determine the association between AR and pathologic complete response (PCR), recurrence free survival (RFS) in TNBC patients treated with neoadjuvant chemotherapy (neoCT). Patients and methods Cross-sectional, retrospective cohort trial. Adult women with stage II-III TNBC, treated with neoCT from 2014 to 2021 were included. Incomplete medical record, AR not-determined, secondary malignant neoplasm were excluded. AR was determined with the VENTANA assay system, &amp;gt; 1% were considered as positive. Statistical analyses included frequencies and range, comparison was done with X2, cox regression model was made for the prognostic association with a two-sided significance level of 0.05 95% CI. RFS were evaluated with Kaplan Meier method and log-rank test. Results 309 patients were analyzed; AR prevalence was 14.6%. Median age was 49 years (21-87), tumor size was 6.3 cm (0.1-22), ductal histology (95.1%) and nuclear-grade 3 (79%), these findings were not different between the AR+ vs AR-. Median Ki67 was 52% within AR+ vs 65% AR- (p=0.05). All patients were treated with neoCT, 14.9% had disease progression, PCR rates were similar among two groups (48.5% vs 42.2%) p=0.78. At a mean follow up of 19 months, 7 recurrences presented in AR+ (15.5%) vs 67 in the AR- (25.4%) p=NS. Median RFS was 54.9 (IC 95% 45.2-64-6) and 65.5 months (IC 95% 60.4-70.7), p=0.3. We analyze the prognostic factors, for RFS we found statistically significant the locally advanced stage OR 5.6 (1.4-22.9), residual cancer burden (RCB) OR 2.8 (2.1-3.9), N stage OR 1.4 (1.1-1.8) and progression during neoCT OR 2.8 (1.5-5.1); and for OS the RCB OR 2.8 (1.9-4.1) and progression during neoCT OR 3.1 (1.5-6.9). Conclusions In this trial the AR expression did not show significant association neither with PCR and RFS; main reasons are the low prevalence of AR expression, high rate of disease progression and high residual cancer burden after neoCT. We found association with other known factors (RCB, N stage, progression during neoCT and locally advanced stage), which are more important factors that determine the bad prognosis of TNBC. Citation Format: Eder Araiza Alvarado, Claudia Haydee Arce Salinas. Association between androgen receptor expression and recurrence free survival among locally advanced triple negative breast. Real world data from a single Institution in Mexico City [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-03-32.
Abstract P5-15-01: Rediscovering IRF5: A prognostic indicator with novel roles in mammary gland development, ribosome biogenesis, tumor initiation, and metastasis
Authors: Betsy Barnes, Zarina Brune, Matthew Rice, Carter Somerville
Journal: Cancer Research (2023)

Abstract Breast cancer is the second leading cause of death for women in the United States. However, only 10% of breast cancers have been linked to inherited genomic mutations. Thus, identifying biomarkers to predict cancer progression and metastasis remains a clear need in the research and medical world. Here, we report a novel role for Interferon Regulatory Factor 5 (IRF5) in mammary gland development, tumorigenesis, and metastasis. Historically, IRF5 has been studied as a transcription factor in the context of genetic risk for autoimmune diseases. However, mining of The Cancer Genome Atlas revealed that loss of IRF5 expression in human breast cancer is significantly linked with progression to high grade carcinoma, increased metastasis, and decreased overall and recurrence-free survival. Supporting these analyses, we demonstrated that female Irf5-/- BALB/c mice have higher incidence of spontaneous atypical ductal hyperplasia (ADH), increased progression to DCIS, and ultimately, increased incidence of IDC. Using qPCR, FISH and IHC, we confirmed that IRF5 is expressed in both luminal and basal myoepithelial cells, but expression is higher in basal cells. Histologic analysis of whole mount preparations of Irf5-/- mammary glands revealed aberrant ductal morphogenesis, characterized by expansion of luminal and basal myoepithelial cells with a loss of organized glandular structure. RNAseq of primary mammary epithelial cells from wild type and Irf5-/- littermate mice showed Irf5-/- mammary epithelial cells to be enriched in ribosome biogenesis pathways, the physiologic consequences of which were demonstrated through increased rates of protein synthesis. Transferring our studies in vivo, we demonstrated that loss of tumor IRF5 expression resulted in decreased tumor-infiltrating lymphocytes and increased pulmonary metastasis in the murine orthotopic 4T1 implantation model. Mechanistically, we found that—as in our studies utilizing primary mammary epithelial cells—IRF5 expression in tumors regulated protein translation and ribosome biogenesis. In light of these findings, we propose IRF5 as a novel prognostic biomarker, loss of which alters mammary gland development, drives tumor initiation and metastasis, and dysregulates mammary epithelial cell protein synthesis. Citation Format: Betsy Barnes, Zarina Brune, Matthew Rice, Carter Somerville. Rediscovering IRF5: A prognostic indicator with novel roles in mammary gland development, ribosome biogenesis, tumor initiation, and metastasis [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P5-15-01.
Abstract P6-11-01: Scaffold attachment factor B1 modulates cholesterol pathways in triple-negative breast cancer
Authors: Meron Ghidey, Divya Murthy, Sukjin Yang, Songyeon Ahn, Jun Hyoung Park, Benny Kaipparettu
Journal: Cancer Research (2023)

Abstract Historically known as a tumor suppressor by estrogen receptor (ER) co-repression in breast cancer (BC), the matrix binding protein Scaffold Attachment Factor B1 (SAFB) binds scaffold or matrix attachment region DNA elements (S/MAR DNA) in eukaryotic DNA. SAFB1 plays a role in cellular stress response, DNA repair, differentiation, and apoptosis. SAFB loss in ER-independent BC and pancreatic cancer (PC) patients resulted in poor survival rates, hinting at the role of SAFB1 as a tumor suppressor. To understand the tumor suppressive mechanism of SAFB1, we performed shRNA-mediated knockdown (KD) of SAFB in PC cell lines and triple-negative breast cancer (TNBC) cells, an aggressive subgroup of BC. Analysis of onco-properties showed an increase in clonogenicity potential and cell proliferation in SAFB KDs in both PDACs and TNBCs cells. Further, RNA-Seq analysis of SAFB KDs in the TNBC cell line revealed activation of the mevalonate (MVA) pathway and the resulting cholesterol biosynthesis as the key metabolic change. Both pancreatic ductal adenocarcinoma (PDACs) and TNBC exhibited higher levels of MVA pathway gene expression upon loss of SAFB. Sterol regulatory element binding proteins (SREBP) 1 and 2 dictate cholesterol biosynthesis, and SREBP2 promotes tumor properties via the MVA pathway. Molecular and metabolic analysis of SAFB KD TNBC showed an increase in lipid droplets and SREBP2 maturation. Using Chromatin Immunoprecipitation and quantitative real-time PCR (ChIP-qPCR) in TNBC we demonstrate the direct binding of SAFB to the SREBP2 promoter region. In addition, byproducts of the MVA pathway have been shown to activate YAP/TAZ-dependent tissue homeostasis and tumorigenesis. We also observed increased YAP1 mRNA levels and decreased YAP1 (Ser127) phosphorylation with SAFB loss in TNBC, explaining the aggressive tumorigenicity gained with SAFB loss. Our study thus far suggests SAFB has overt control over the SREBP2-MVA-YAP1 pathway, and loss of SAFB results in an enhanced tumor phenotype. Citation Format: Meron Ghidey, Divya Murthy, Sukjin Yang, Songyeon Ahn, Jun Hyoung Park, Benny Kaipparettu. Scaffold attachment factor B1 modulates cholesterol pathways in triple-negative breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P6-11-01.
Abstract P6-11-02: Mitochondria-Nuclear Crosstalk Regulates the WNT Pathway in Triple-Negative Breast Cancer
Authors: Sukjin Yang, Jun Hyoung Park, Suna Kim, Meron Ghidey, Benny Kaipparettu
Journal: Cancer Research (2023)

Abstract Compared to hormone receptor (HR) positive breast cancer (BC), basal or triple-negative BC (TNBC) suffers a poor prognosis caused by a limited understanding of its driver signaling pathways. We used the transmitochondrial cybrid approach to understand the metabolic reprogramming and mitochondria-nuclear crosstalk in metastatic TNBC. In cybrids, mitochondria from cancer and benign cells are compared under a commonly defined nuclear background. Using cybrid-based discovery and its validation in cell lines, patient-derived xenografts, and clinical data, we have previously reported the activation of fatty acid oxidation (FAO) in metastatic TNBC. Recently, we developed a unique gene (DEG) signature by integrating gene expression data from cybrids with different omnibus databases such as TCGA and METABRIC. Our DEG could effectively distinguish the PAM50 subtypes of BC. Further analyses nominated negative regulation of the canonical WNT signaling pathway as one of the major pathways altered by mitochondrial character. The WNT pathway is known to regulate cell signaling, metabolism, epithelial-mesenchymal transition (EMT), and cancer stemness. Cybrids with benign mitochondria showed transcriptional activation of negative WNT regulators, including DKK1, SOST, DAB2, and CAV1. Citrate is a key metabolite from the tricarboxylic acid cycle (TCA cycle) and is an intermediate of many other metabolic pathways. Analysis of TNBC cybrids, cell lines, and BC tissues suggest that in TNBC, citrate levels are increased with the activation of CPT1A, the rate-limiting enzyme of FAO. We confirmed the reduction of the beta-catenin protein in TNBC cells after pharmacological and genetic inhibition of CPT1A and mitochondrial citrate transporter (SLC25A1). We further analyzed the gene set enrichment analysis (GSEA) using gene expression data developed from short and long-term CPT1A inhibited TNBC cells and observed that the FAO alters polycomb repressive complex 2 (PRC2) activity. PRC2 is a critical modulator of the H3K27 methylation pattern as well as pathways related to cancer stemness, including WNT/beta-catenin and Hedgehog (SHH) pathways. These results suggest that the mitochondrial FAO transcriptionally inhibits WNT antagonist genes through repressive histone modification and consequently activates the canonical WNT pathway and cancer stemness. Overall, our current observations provide new insights into the regulation WNT pathway by mitochondria-nuclear crosstalk in TNBC. Citation Format: Sukjin Yang, Jun Hyoung Park, Suna Kim, Meron Ghidey, Benny Kaipparettu. Mitochondria-Nuclear Crosstalk Regulates the WNT Pathway in Triple-Negative Breast Cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P6-11-02.
Abstract P3-07-24: Role of tumor cell-derived lactic acid in the PD-1/PD-L1 blockade resistant tumor
Authors: Wonkyung Oh, Seung-Oe Lim
Journal: Cancer Research (2023)

Abstract Immune checkpoint blockade therapy targeting the PD-1/PD-L1 axis (PD-1/PD-L1 blockade therapy) has shown remarkable clinical impact in multiple cancer types. Despite the recent success of PD-1/PD-L1 blockade therapy, acquired resistance, emerging as late relapses or recurrences, has been reported in the long-term follow-up of clinical trials. The altered metabolic activity of cancer cells shapes the anti-tumor immune response by affecting the activity of immune cells. In particular, glycolytic metabolites, such as glucose and lactate, regulate T cell proliferation and function. However, it remains mostly unknown how the altered metabolic activity of cancer cells impacts the therapeutic efficacy of, and resistance to, PD-1/PD-L1 blockade therapy. Here, we found that increased lactic acid functionally contributes to an immunosuppressive tumor microenvironment in the PD-1/PD-L1 blockade therapy resistant tumors through decreasing PD-L1 and PD-L1 antibody interaction. Furthermore, combinating PD-L1 targeting with our PD-L1-antibody-drug conjugate (ADC) and reducing lactic acid by an MCT-1 inhibitor, AZD3965, within the tumor microenvironment effectively eradicated the resistant tumor cells. Together, our results suggest a new combination treatment strategy to improve the therapeutic efficacy of immune checkpoint blockade therapies Citation Format: Wonkyung Oh, Seung-Oe Lim. Role of tumor cell-derived lactic acid in the PD-1/PD-L1 blockade resistant tumor [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P3-07-24.
The effect of a preconception and antenatal nutritional supplement on children's BMI and weight gain over the first 2 years of life: findings from the NiPPeR randomised controlled trial
Authors: Jaz Lyons-Reid, José G B Derraik, Timothy Kenealy, Benjamin B Albert, J Manuel Ramos Nieves, Cathriona R Monnard, Phil Titcombe, Heidi Nield, Sheila J Barton, Sarah El-Heis, Elizabeth Tham, Keith M Godfrey, Shiao-Yng Chan, Wayne S Cutfield
Journal: The Lancet Global Health (2023)
Abstract P6-03-02: Social determinants, food deserts, and their combined contribution to breast cancer mortality
Authors: Kara McCormack
Journal: Cancer Research (2023)

Abstract Recent studies have found that both food deserts (FD) and lower socio-economic status (SES) are individually associated with increased breast cancer mortality in the US. However, further work is needed to investigate their combined contribution to breast cancer mortality. Furthermore, valid inference for area-level disease mapping requires careful consideration of spatial clustering. In our study, we utilize data from the USDA Food Access Research Atlas and the American Community Survey. Breast cancer mortality data come from the National Center of Health Statistics 2014 report. We consider a latent class mixture model to determine deprivation categories which incorporate six SES proportion variables (no car, poverty, no HS graduation, crowded housing, unemployment, crowded housing), two FD (Low income and &amp;gt; 1 mile from supermarket and receiving snap benefits and &amp;gt; 1 mile from supermarket) variables. Our latent class model has three levels: Low, Moderate, and High, making up 36.6%, 45.6%, and 17.8% of US counties, respectively. We then incorporated these levels as a fixed effect in a Bayesian hierarchical spatial negative binomial model using R-INLA. In this model, we account for both spatially structured and unstructured effects. Counties classified as “High” on our deprivation categories were associated with a 50% increase in breast cancer mortality rates (95% CrI: [1.12, 2.02]). Also, the county proportion of women &amp;gt;65 was significantly associated with 1.42 times higher breast cancer mortality (95% CrI [1.37, 1.42]). Policies that allow for access in the face of deprivation may contribute to lower overall breast cancer mortality. Citation Format: Kara McCormack. Social determinants, food deserts, and their combined contribution to breast cancer mortality [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P6-03-02.